Derivatives of z



Patented Aug. 17, 1937 1 UNITED STATES wean? PATENT OFFICE Otto Sohnider, Basel, Switzerland, assig-nor to Hofimann-La Roche Inc., Nutley; N. J., a corporation of New Jersey No Drawing. Application July 14, 1936, Serial 7 No. 90,609. In Ger 4 Claims.

By condensing malonic ester with fl-aminocrotonic-ester dihydroxy-fi-methyl-pyridine-carboxyl-acid-ester is obtained which may be converted in a simple manner into dihydroxy-G- 5 methyl-pyridine (Berichte der Deutschen Chemialkalis, but also in strong acids; their solutions 5 schen Gesellschaft vol. 31, 1898, page 766 ff.). By produce no colouration with ferric chloride. By the same process and starting from the catalytic hydrogenation the unsaturated alkyl mono-alkyl-malonic-esters 2,4-dihydroXy-3-alradicles are converted into saturated radicles.

kyl-fi-rnethyl-pyridines are obtained. ZA-dihy- They are readily 'crystallizable compounds of droxy-pyridine has likewise been prepared in a rather low melting point. The simple representa-. similar manner (Berichte der Deutschen Chemitives of thisgroup of compounds may be disschen Gesellschaft vol. '31, 1898, page 1682 ff.). tilled under, reduced pressure. Without p The diethyl-ether has beenprepared by way of sition. All of these compounds are odourless.

the silver salt;.att'empted alkylation of the They are to be used for therapeutical purposes as 15 nitrogen atom was unsuccessful (Berichte der they h v p rifi i n. m f hem v n Deutschen Chemischen Gesellschaft vol. 31, 1898, in Very small doses. pages 1689 and 1690) If, on the other hand, the Example 1 alkali salts are alkylated by any of the usual methods, the alkyl group becomes attached to 111 p r s y Weight of Y y-pll d e 20 the nitrogen atom. Unlike the starting material are dissolved in 600 parts by weigh f W r by the compounds thus obtained are insoluble in the addition of 129 parts by Weight O a alkali. sodium hydroxide solution. 121 parts by weight It has now been found that it is possible to atof allyl bromide and 0.5 part by weight of coptach two'alkyl groups in the 3-position to the per DO are then added With thorough S irring.

pyridine derivatives,mentioned, without alkylat- After about half an hour and after slight evoluing the nitrogen, if allyl halides are allowed to retion of heat t e ture becomes neutral. A act with the alkali salts of ZA-dihydroxy-pyridine further 129 parts by weight of 31% sodium or 2,4-dihydroxy-6-methyl-pyridine or their dehydroxide solution and 121 parts by weight of rivatives mono alkylated in the 3-position, in allyl-bromide are added, whereby further heat is 30 aqueous solution in the presence of copper or copevolved. The reaction is terminated after about 20 per compounds. Instead of allyl-halides their deminutes. After cooling the precipitated 2,4-dirivatives substituted in the 2-position (bromo- 0x0-3,3-diallyl-tetrahydro-pyridine is filtered 01f, allyl-bron'iide or methyl-allyl-chloride.) may also dried and distilled under strongly reduced presd 7 sure. The distillate is crystallized from benzene 35 The starting compounds probably react accordwith addition of petroleum ether. It forms 35 ing to the following 4 tautomeric formulae: colourless crystals melting at 81-82 C. The

, OH on 00 H: /oo /H c 40 cu C-dt on o CH o a on c-R 40 l a l P l l R l o o-OH 0 0-011 o co o o I II III Iv In these formulae R represents hydrogen or alkyl,

R1 hydrogen or methyl. The new compounds cannot, like the starting materials used, be designated as derivatives of dimany August 28, 1935 hydroxy-pyridine; they must be hydroxy-oxoor still more likely dioXo-compounds, that is to say the substituents must occupy the. position shown in Formulae II and III. They are soluble in boiling point lies between 208 and 210 C. under 14 mm. pressure. The compound is readily soluble in organic solvents, but in petroleum ether and in water it is onlyslightly soluble. By suit- 50 able catalytic hydrogenation the corresponding dipropyl compound melting at 92-93 C. is obtained.

Example 2 167 parts by weight of. 2,4-dihydroxy-3-npropyl-6-methyl-pyridine are dissolved in 1000 parts by volume of n-sodium hydroxide solution and quickly stirred. Then 121 parts by weight of 10 allyl bromide and a solution of 1.5 parts by weight of copper sulphate in l5parts by weight of water are added. There is a slight evolution of heat and the conversion is completed in about half an hour without further manipulation.

benzene, the benzene layer removed and dis.- tilled. The methyl-tetrahydro-pyridine distils under 14 mm. pressure at 213-215 C. The distillate solidifies it melts at 73-74 C.

Ewample 3 under reduced pressure (boiling point 208-210 C. .:under 14 mm. pressure) by recrystallization from dibutyl ether. It melts at 84-85'C. By suitable catalytic hydrogenation the corresponding dipropyl compound melting zit-104 C. is obtained.

: Example 4 solution are diluted with 1000 parts by weight of water and 167 parts by weight of 2,4-dihydroxy- 3-n-propyl-6-methyl-pyridine are dissolved therein. 200 parts by weight of bromo-allyl-bromide and 1 part by weight of copper powder -are.then

added and the product is heated for about 4 hours to 60 C. with continuous stirring until the v mixture becomes neutral. The 2,4-,dioxo+3,3-p-

5o bromo-allyl-n-propyl-tetrahydro-pyridine is separated from the liquid and maybe purified .by dissolving in dilute alkali, precipitating with carbon dioxide and crystallizing from petroleum ether. It melts at 128-124 C.

Example 5 153 parts by weight of 2,4-dihydroxy-3-ethyl-6- methyl-pyridine are dissolved in an equivalent of n-sodiumhydroxide. and thoroughly stirred with 091 parts by weight of isobutylene chloride (/3- methyl-allyl-chloride) and 0.5 part by weight of copper powder for 3 hours at about 40 C. The 2,4-dioxo-3,3-ethyl-isobute nyl- 6 -methyl-tetrahydro-pyridine thus obtained is separated and '5. purified in the manner described in Example 1.

It melts at -101 C.

Example 6 To a solution of parts by weight of 2,4-

70 dihydroxy-G-methyl-pyridine in 1100 parts by -weight of water containing 40 parts by weight of sodium hydroxide; 0.7 part .by weight of copper acetateand 121 parts 'by weight of allyl bromide are added while thoroughly'stirring. When the 75 reaction which is accompanied by slight evolution The 15 product is extracted with 500 parts by weight of 2,4-dio xo-3,3'-n-propy1-a llyl-6-- and may be recrystallized from petroleum ether;

dihydroxy-6-methyl-pyridine in 955 parts-by.

,The conversion is complete.

129 parts by weight of 31% sodiumhydroxide.

of heat, is complete, 116 parts by weight of 34.5% sodium hydroxide and again 121 parts by weight of allyl bromide are added with continued stirring. Further allylation occurs with evolution of heat. After about an hour the precipitated 2,4 -dioxo- 3,3-dial1yl-6-methyl-tetrahydro-pyridine may be purified in the manner described in Example 3.

Example 7 209 parts by weight of 2,4-dihydroxy-3-nhexyl-6-methyl-tetrahydro-pyridine are dissolved in 1000 parts by volume of n-potassium hydroxide. To the stirred solution 0.5 part by weight of copper-bronze and 121 parts by weight of allyl bromide are added. Reaction sets in with slight evolution of heat. When the solution has become neutraLthe precipitated oil is taken up in benzene and after the benzene has been driven off the2,4-dioxo-3,3-n hexyl-allyl-6-methyl-tetrahydro-pyridine remains as an oil and is distilled in 1; vacuo. It boils under 13 mm. pressure at 231- 234 C. The distillate slowly solidifies; it melts Example 8 A solution of parts by weight of 2,4-dihydroxy-3-allyl-6-methyl-tetrahydro-pyridine, in

1000 partsby weight of water is stirred with 116 1 parts by weight of 34.5% sodium hydroxide. To

the clear solution 0.5 part by weight of copper powder and 76.5 parts by weight of allyl chloride,

are added while continually stirring. The allyla tion sets in with slight evolution of heat. The conversion product is identical with the 2,4-dioxo- 3,3-diallyl-G-methyl-tetrahydro-pyridine of Example 3.

Example 9 In 1000 parts by volume 01' n-sodium hydroxide 179 parts by weight of 2,4-dihydroxy-3-isobu= tenyl-6-methyl-tetrahydro-pyridine are dissolved" While stirring. If 0.4 part by weight of copper powder and 121 parts by weight'ofallyl bromide are added, the conversion, immediately sets in. After about three quarters of an hour the com.- pletion of the reaction is indicated by neutral reaction.

arated from the aqueous liquor and re-dissolved from 60% alcohol. It melts at 144-145 C.

Example 10 153 parts by weight of 2,4-dihydroxy-3-isopropyl-tetrahydro-pyridine are dissolved in 900 parts by weight of water containing 116 parts by weight of 34.5% sodium hydroxide, while thoroughly stirring. Then 121 parts by weight of allyl bromide and 0.5 part by weight of copper powder are added, after which reaction sets in with slight evolution of heat. allyl-tetrahydro-pyridine is taken up in benzene.

By extracting the benzene solution with 1000 parts by volume of n-sodium hydroxide the product is again removed from the benzene and precipitated from the filtered clear solution with dilute hydrochloric acid. After drying it is'redissolved from high-boiling petroleum ether. 5- It melts at 86-87 C.

I claim: 1. Compounds of the formula cfis c The precipitated 2,4-dioxo-3,3-isobu-" tenyl-allyl-6-methyl-tetrahydro-pyridine is s'ep-.

The 2,4-dioxo3,3-isopropyl-' wherein R is a. radical selected from the group consisting of hydrogen and alkyl radicals, and R" and R' are alkyl radicals, at least one of which is selected from the group consisting of allyl and substituted allyl radicals, the compounds being soluble in alkalies and strong acids producing in solution no coloration with ferric chloride, and having a soporific action.

2. The 2,4-dioxo-3,3-diallyl-6-methy1-tetrahydro-pyridine melting at 84-85" C., boiling at 208- 210 C. under 14 mm. pressure and forming by suitable catalytic hydrogenation the corresponding dipropyl compound melting at 104 C.

3. The process for the manufacture of derivatives of 2,4-dioxo-tetrahydro-pyridine which consists in allowing allyl halides of the general formula CH2=CR,-CH2Hal, in which R is hydrogen, halogen or methyl, to react with the alkali salts of 2,4-dihydroxy-pyridines of the general formula on in which R is hydrogen or methyl, R" hydrogen or alkyl, in aqueous solution in the presence of copper or copper compounds.

4. The process for the manufacture of 2,4-dioxo 3,3 diallyl 6 methyl-tetrahydro-pyridine which consists in allowing allyl bromide to react with the sodium salt of 2,4-dioxo-6-methyl-pyridine in aqueous solution in the presence of copper powder.

OTTO SCHNIDER. 

